title: Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome.
abstract: Genetic-dissection studies carried out with Down syndrome (DS) murine models point to the critical contribution of Dyrk1A overexpression to the motor abnormalities and cognitive deficits displayed in DS individuals. In the present study we have used a murine model overexpressing Dyrk1A (TgDyrk1A mice) to evaluate whether functional CNS defects could be corrected with an inhibitory RNA against Dyrk1A, delivered by bilateral intrastriatal injections of adeno-associated virus type 2 (AAVshDyrk1A). We report that AAVshDyrk1A efficiently transduced HEK293 cells and primary neuronal cultures, triggering the specific inhibition of Dyrk1A expression. Injecting the vector into the striata of TgDyrk1A mice resulted in a restricted, long-term transduction of the striatum. This gene therapy was found to be devoid of toxicity and succeeded in normalizing Dyrk1A protein levels in TgDyrk1A mice. Importantly, the behavioral studies of the adult TgDyrk1A mice treated showed a reversal of corticostriatal-dependent phenotypes, as revealed by the attenuation of their hyperactive behavior, the restoration of motor-coordination defects, and an improvement in sensorimotor gating. Taken together, the data demonstrate that normalizing Dyrk1A gene expression in the striatum of adult TgDyrk1A mice, by means of AAVshRNA, clearly reverses motor impairment. Furthermore, these results identify Dyrk1A as a potential target for therapy in DS.
authors.affiliation: Programa Gens i Malaltia. Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomèdica de Barcelona-PRBB, Barcelona 08003, Spain.
authors.forename: Jon
authors.initials: J
authors.lastname: Ortiz-Abalia
authors.forename: Ignasi
authors.initials: I
authors.lastname: Sahún
authors.forename: Xavier
authors.initials: X
authors.lastname: Altafaj
authors.forename: Núria
authors.initials: N
authors.lastname: Andreu
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D000229:Dependovirus / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases